Heat shock protein inhibitors increase the efficacy of measles virotherapy.

Oncolytic measles virus strains have activity against multiple tumor types and are currently in phase I clinical testing. Induction of the heat shock protein 70 (HSP70) constitutes one of the earliest changes in cellular gene expression following infection with RNA viruses including measles virus, and HSP70 upregulation induced by heat shock has been shown to result in increased measles virus cytotoxicity. HSP90 inhibitors such as geldanamycin (GA) or 17-allylaminogeldanamycin result in pharmacologic upregulation of HSP70 and they are currently in clinical testing as cancer therapeutics. We therefore investigated the hypothesis that heat shock protein inhibitors could augment the measles virus-induced cytopathic effect. We tested the combination of a measles virus derivative expressing soluble human carcinoembryonic antigen (MV-CEA) and GA in MDA-MB-231 (breast), SKOV3.IP (ovarian) and TE671 (rhabdomyosarcoma) cancer cell lines. Optimal synergy was accomplished when GA treatment was initiated 6-24 h following MV infection. Western immunoblotting confirmed HSP70 upregulation in combination-treated cells. Combination treatment resulted in statistically significant increase in syncytia formation as compared to MV-CEA infection alone. Clonogenic assays demonstrated significant decrease in tumor colony formation in MV-CEA/GA combination-treated cells. In addition there was increase in apoptosis by 4,6-diamidino-2-phenylindole staining. Western immunoblotting for caspase-9, caspase-8, caspase-3 and poly(ADP-ribose) polymerase (PARP) demonstrated increase in cleaved caspase-8 and PARP. The pan-caspase inhibitor Z-VAD-FMK and caspase-8 inhibitor Z-IETD-FMK, but not the caspase-9 inhibitor Z-IEHD-FMK, protected tumor cells from MV-CEA/GA-induced PARP activation, indicating that apoptosis in combination-treated cells occurs mainly via the extrinsic caspase pathway. Treatment of normal cells, such as normal human fibroblasts, however, with the MV-CEA/GA combination, did not result in cytopathic effect, indicating that GA did not alter the MV-CEA specificity for tumor cells. One-step viral growth curves, western immunoblotting for MV-N protein expression, QRT-PCR quantitation of MV-genome copy number and CEA levels showed comparable proliferation of MV-CEA in GA-treated vs -untreated tumor cells. Rho activation assays and western blot for total RhoA, a GTPase associated with the actin cytoskeleton, demonstrated decrease in RhoA activation in combination-treated cells, a change previously shown to be associated with increase in paramyxovirus-induced cell-cell fusion. The enhanced cytopathic effect resulting from measles virus/GA combination supports the translational potential of this approach in the treatment of cancer.

Pursuing integration of performance measures into electronic medical records: beta-adrenergic receptor antagonist medications.

OBJECTIVE: Electronic medical records seldom integrate performance indicators into daily operations. Assessing quality indicators traditionally requires resource intensive chart reviews of small samples. We sought to use an electronic medical record to assess use of beta-adrenergic antagonist medications (beta-blockers) following myocardial infarction, to compare a standardized manual assessment with assessment using electronic medical records, and to discuss potential for future integration of performance indicators into electronic records. DESIGN: Cross-sectional data analysis. SETTING: An urban academic medical center. PARTICIPANTS: US Medicare beneficiaries 65 years of age or older, admitted to hospital with myocardial infarction between 1995 and 1999. MEASUREMENTS AND MAIN RESULTS: Manual chart review was compared with a computer driven assessment of electronic records. Administration of beta-blockers and cases excluded from use of beta-blockers were measured, based on Medicare criteria. Among 4490 older adults, 391 (4%) of 9018 hospital admissions contained codes for myocardial infarction. In 323 (83%) of the 391 hospital admissions, criteria for excluding beta-blockers were met; 235 (60%) were excluded due to heart failure. Of 68 hospital admissions for myocardial infarction that did not meet exclusion criteria, physicians prescribed beta-blockers in 49 (72%) on admission and 42 (62%) at discharge. Compared with manual chart review, electronic review had a sensitivity of 83-100% and led to fewer false negative findings. CONCLUSIONS: An electronic medical records system can be used instead of chart review to measure use of beta-blockers after myocardial infarction. This should lead to integration of real time automated performance measurement into electronic medical records.

Computer reminders to implement preventive care guidelines for hospitalized patients.

BACKGROUND: Hospitalizations are an opportunity to provide preventive care. OBJECTIVE: To determine if computer reminders, which we have shown to be effective in our ambulatory care setting, increasing the provision of inpatient preventive care. METHODS: Randomized, controlled trial on the general medicine inpatient service of an urban, university-affiliated public hospital. Study subjects were 78 house staff rotating on the 6 general medicine services. The intervention was reminders to physicians printed on daily rounds reports about preventive care for which their patients were eligible, and suggested orders for preventive care provided through the physicians' workstations. The preventive care guidelines were derived from the US Preventive Care Task Force recommendations. Compliance with preventive care guidelines and house staff attitudes toward providing preventive care to hospitalized patients were the main outcome measures. RESULTS: No significant differences were seen between intervention and control physicians in compliance with preventive care guidelines in the aggregate or when individual preventive care actions individual preventive care actions were analyzed. This was true even though most physicians endorsed providing most kinds of preventive care for hospitalized patients. CONCLUSIONS: Despite past success in increasing preventive care in the outpatient setting, we were unable, using a moderately intensive intervention, to increase the provision of preventive care during hospitalizations. The physicians providing care during the hospitalization were not the patients' primary care physicians, which proved to be an important barrier. More intensive interventions, or more direct linkages between inpatient and outpatient care providers, may be required to overcome this resistance.

Unexpected hospital admissions among patients with diabetes mellitus.

In a search for a new way to recognize the patients who are at higher risk of unexpected hospitalizations, the characteristics of patients with diabetes mellitus were examined after their last office visit prior to hospitalization. Six characteristics contributed significantly in distinguishing 256 patients who were subsequently hospitalized from 512 patients who were not. The six characteristics included the following: frequent emergency room visits, low serum albumin level, cardiomegaly, anemia, hypotension, and hyperglycemia. The sensitivity of prediction was 43.2%, specificity was 77.4%, and the relative risk by odds ratio was 2.60:1. The intensity of care, as estimated by the level of the provider, and the intended intensity of care, as measured by the scheduled return-visit interval, were not clinically consistent with the magnitude of risk. The characteristics of patients at higher risk of unexpected hospitalizations were identified and provide a direction for increased intensity of ambulatory care.

Tannin interactions with a full-length human salivary proline-rich protein display a stronger affinity than with single proline-rich repeats.

The protein IB5 has been purified from human parotid saliva. This protein contains several repeats of a short proline-rich sequence. Dissociation constants have been measured at several discrete binding sites using 1H-NMR for the hydrolysable tannins (polyphenols) beta-1,3,6-tri-O-galloyl-D-glucopyranose, beta-1,2,4,6-tetra-O-galloyl-D-glucopyranose and beta-1,2,3,4,6-penta-O-galloyl-D-glucopyranose and the condensed proanthocyanidin (--)-epicatechin. The dissociation constants for trigalloyl glucose and pentagalloyl glucose were 15 X 10(-5) and 1.7 X 10(-5) M, respectively, which are 115 and 1660 times stronger than those previously measured under the same conditions for a single repeat of a mouse salivary proline-rich protein. The increase in affinity is ascribed to intramolecular secondary interactions, which are strengthened by the rigidity of the interacting molecules.

Beta-adrenergic regulation of beta-actin mRNA abundance in mouse parotid glands by a post-transcriptional mechanism.

In the first 24 h after a single injection of the beta-adrenergic agonist isoprenaline to mice, the level of beta-actin mRNA in the parotid glands increased significantly above that observed in untreated mice. The increase was transient, reaching 11 times the normal level 18 h after treatment and declining thereafter. Repeated daily doses of isoprenaline did not result in any further increase in beta-actin mRNA. Nuclear transcription experiments showed that there was no increase in the transcription rate of the beta-actin gene 8 h after an injection of isoprenaline, although beta-actin mRNA levels were increasing at this time. Immunoblotting revealed an increase in beta-actin protein in parotid gland samples after isoprenaline treatment, although the increase was not to the same extent as the mRNA, perhaps indicating that degradation of beta-actin had also increased. Using immunocytochemistry it was found that beta-actin was located mainly in the apical cortex of the normal acinar cell. There was a significant decrease in cortical beta-actin 24 h after isoprenaline treatment, suggesting that the beta-actin was under the process of redistribution. From these data we propose that isoprenaline caused an increase in beta-actin synthesis by a posttranscriptional mechanism and a redistribution of beta-actin in preparation for the well-known subsequent change in morphology and function of the parotid glands.

Isoprenaline-induced and constitutive members of a proline-rich protein sub-group from mouse parotid glands studied with monoclonal antibody NAL1.

Members of the proline-rich protein (PRP) family of mouse parotid glands were analysed before and after stimulation with the beta-agonist isoprenaline by using a monoclonal antibody raised against the induced PRP A3(0) (GP-27). Antibody NAL1 reacted strongly with isoprenaline-induced B-type PRP precursors and their salivary counterparts, but not against the A-type PRPs A1(0) (Gp-66) and A2(0) (GP-45) or human salivary proteins, and it is likely that NAL1 recognizes a proline-rich repeat variant unique to this group of rodent PRPs. PRP-related antigens were observed in the parotid glands (N1(0) and N2(0] and saliva of normal mice. The antigens were located immunocytochemically in secretory granules of parotid acinar cells of both normal and isoprenaline-stimulated mice. The total amount of PRP antigens increased 16-fold from 2.5 to 40% of parotid protein after 10 days of isoprenaline treatment, as estimated by enzyme-linked immunosorbent assay. Immunoblotting showed that new PRP species appeared during the period of increase. After treatment with isoprenaline, B-type PRPs appeared first, followed by A3(0) and another member of the family. These results show that the mouse PRP family is larger than previously thought and can be divided immunologically into sub-groups. That a subset of PRPs are produced in the normal mouse indicates that there is differential beta-adrenergic regulation within the family, and also has implications for the role of PRPs in the normal maintenance of healthy dentition and other processes.

Symptoms in hospitalized patients: outcome and satisfaction with care.

PURPOSE: Physical symptoms are responsible for substantial morbidity in outpatients. We assessed symptoms in patients admitted to a hospital to determine their frequency, persistence at discharge, and the relation between symptom outcome and satisfaction with care. METHODS: During a 12-month period, 2,126 hospitalized medical patients completed a study interview within 2 hours of admission. More than half (n = 1,168) of the patients were re-interviewed within 24 hours of discharge. We ascertained the presence and severity of 11 physical symptoms, as well as activities of daily living, mobility, mood, self-rated health, physiologic severity of illness, satisfaction with care, and length of stay. RESULTS: Symptoms were common at the time of hospital admission, particularly fatigue (80% of patients), dyspnea (60%), cough (51%), dizziness (51%), headache (47%), chest pain (46%), and nausea or vomiting (43%). Individual symptoms failed to resolve by hospital discharge approximately 25% to 50% of the time. The three most prominent predictors of persistence of symptoms were shorter length of stay, severity of the symptom on admission, and total symptom count. Patient satisfaction with care was associated with total symptom severity score at discharge and the degree of symptomatic improvement that had occurred during hospitalization. CONCLUSION: Because symptoms are common at discharge and associated with decreased satisfaction with care, asking about them would be a reasonable way to enhance patient-oriented care.

Comparison of seminal vesicle secretory proteins of rodents using antibody and nucleotide probes.

The copulatory vaginal plug is a conspicuous feature of rodent reproduction. The five major seminal vesicle secretory proteins of Rattus norvegicus (proteins I-V), which form the copulatory plug, constitute a closely related androgen-regulated family that appears to share a common evolutionary origin. The relationships between these rat proteins and the major seminal vesicle proteins of other rodents were explored using antibodies specific for the individual rat proteins. Immunoblotting of proteins separated by SDS-PAGE showed that the vesicular proteins of R. rattus are identical to those of R. norvegicus except for an additional protein related to protein III. No differences were seen in inbred and outbred strains of R. norvegicus. Of the major proteins of Mus musculus, one showed strong homology with rat protein II and three others were weakly homologous to proteins I, IV (or S) and V (or F); none showed homology to rat protein III. The only homology between the vesicular proteins of Mesocricetus auratus (Syrian hamster) and Meriones ungulatus (Mongolian gerbil) was with rat protein II while those of Cavia porcellus (guinea pig) showed no homology at all with the rat proteins. In addition, cDNA probes for rat genes IV and V both detected weak homologues in seminal vesicle RNA from mice but not guinea pigs.(ABSTRACT TRUNCATED AT 250 WORDS)

Androgen-regulated proteins of rat seminal vesicle secretion constitute a structurally related family present in the copulatory plug.

All the major androgen-regulated secretory proteins of rat seminal vesicles have been purified in high yield from polyacrylamide gels using electroelution. In the process a sixth previously undocumented protein has been identified. Amino acid compositions of all the proteins are very similar and highly unusual, being high in lysine and arginine, and with 40-50% of the residues accounted for by serine, glycine and glutamate/glutamine. N-Terminal amino acid sequences for 3 of the proteins show that they are clearly the products of related genes. At least one of the other proteins is N-terminally blocked in vivo. Antibodies specific for each protein have been raised and provide evidence of structural similarity between the proteins. The antibodies were also used in immunofluorescence histochemistry with the rat copulatory plug, showing for the first time that all the major proteins of seminal vesicle secretion are components of this reproductive structure.

Validity and utility of patient-reported health measures on hospital admission.

Patient perceptions of their health are often inadequately captured and explored on hospital admission where physiologic and other objective measures are the focus of attention. Therefore, we conducted a prospective study to develop and validate measures of several domains of patient-reported health status at the time of admission to a general medicine inpatient service, and to determine the value of these new measures in predicting length of stay (LOS). Within 2 hours of the time that a decision to admit a patient was made, research assistants delivered a structured interview that captured patients' current symptoms, functional status, mood, and perceived health. Interviews were conducted between 8 a.m. and 11 p.m., 5 days per week from July 1996 through June 1997. During this time, there were 3621 unique patients admitted to the medicine service; 2672 (74%) of these patients were eligible for an interview. Eighty-eight percent of the 2672 eligible patients were interviewed. In addition to the patient-reported measures captured through the structured interview, the acute physiology score (APS) of the APACHE II was calculated for all subjects. The internal consistency (i.e., Cronbach's alpha) of the scales was 0.76 or greater and concurrent validity (i.e., correlation) of the patient-reported measures with the APS was 0.01 to 0.13. Overall perceived health was correlated 0.20 to 0.45 with symptoms and functional status, and was correlated 0.07 with the APS. The patient-reported measures performed comparably to the APS in predicting LOS (R-square = 0.08). When the patient-reported measures and the APS were included in the same model, the R-square was 0.14. These analyses suggest that patient-reported measures of health and function on admission hold validity, and that responses to as few as 15 questions can provide data that may help to explain differences in length of a hospital stay.

A data base approach to laboratory computerization.

The Regenstrief Clinical Laboratory System (RCLS) has been operational since 1975 at Wishard Memorial Hospital in Indianapolis, Indiana. The clinician support, use of a true data base management system, and the user interfaces distinguish this system from many commercially available laboratory systems. Physician reports include laboratory, clinical (e.g., physical examination), pharmacy, and radiology data in a single, compact flow sheet. The system can search patient medical records for conditions that may require corrective action and inform physicians of the reasons these actions should be considered. The RCLS data base and its flexible data retrieval capabilities provide a variety of effective technics for monitoring laboratory utilization. The site-specific modifications required to transport this system do not require reprogramming. Important laboratory support features include highly "user friendly" design, multiple specimen numbering sequences, large amounts of free text, reports that can be tailored by non-programmer personnel, CAP accounting statistics, online instrument interfaces, and extensive online instructional facilities.

The barriers to electronic medical record systems and how to overcome them.

Institutions all want electronic medical record (EMR) systems. They want them to solve their record movement problems, to improve the quality and coherence of the care process, to automate guidelines and care pathways to assist clinical research, outcomes management, and process improvement. EMRs are very difficult to construct because the existing electronic data sources, e.g., laboratory systems, pharmacy systems, and physician dictation systems, reside on many isolated islands with differing structures, differing levels of granularity, and different code systems. To accelerate EMR deployment we need to focus on the interfaces instead of the EMR system. We have the interface solutions in the form of standards: IP, HL7/ASTM, DICOM, LOINC, SNOMED, and others developed by the medical informatics community. We just have to embrace them. One remaining problem is the efficient capture of physician information in a coded form. Research is still needed to solve this last problem.

Continuous speech recognition for clinicians.

The current generation of continuous speech recognition systems claims to offer high accuracy (greater than 95 percent) speech recognition at natural speech rates (150 words per minute) on low-cost (under $2000) platforms. This paper presents a state-of-the-technology summary, along with insights the authors have gained through testing one such product extensively and other products superficially. The authors have identified a number of issues that are important in managing accuracy and usability. First, for efficient recognition users must start with a dictionary containing the phonetic spellings of all words they anticipate using. The authors dictated 50 discharge summaries using one inexpensive internal medicine dictionary ($30) and found that they needed to add an additional 400 terms to get recognition rates of 98 percent. However, if they used either of two more expensive and extensive commercial medical vocabularies ($349 and $695), they did not need to add terms to get a 98 percent recognition rate. Second, users must speak clearly and continuously, distinctly pronouncing all syllables. Users must also correct errors as they occur, because accuracy improves with error correction by at least 5 percent over two weeks. Users may find it difficult to train the system to recognize certain terms, regardless of the amount of training, and appropriate substitutions must be created. For example, the authors had to substitute "twice a day" for "bid" when using the less expensive dictionary, but not when using the other two dictionaries. From trials they conducted in settings ranging from an emergency room to hospital wards and clinicians' offices, they learned that ambient noise has minimal effect. Finally, they found that a minimal "usable" hardware configuration (which keeps up with dictation) comprises a 300-MHz Pentium processor with 128 MB of RAM and a "speech quality" sound card (e.g., SoundBlaster, $99). Anything less powerful will result in the system lagging behind the speaking rate. The authors obtained 97 percent accuracy with just 30 minutes of training when using the latest edition of one of the speech recognition systems supplemented by a commercial medical dictionary. This technology has advanced considerably in recent years and is now a serious contender to replace some or all of the increasingly expensive alternative methods of dictation with human transcription.

Demonstrating the effects of an IAIMS on health care quality and cost.

The importance of demonstrating the effect of integrating electronic medical records into clinical practice, and methods for conducting the studies necessary to do so, are presented as a model that may be applicable to other aspects of the Integrated Advanced Information Management System (IAIMS). Integrated electronic medical record (EMR) systems offer the prospect of both improving the quality of health care by reducing variation in processes and outcomes and lowering its costs. Because such systems are expensive and require time-consuming re-engineering of health care delivery, demonstrating effectiveness should be part of system development. The expected benefits should be demonstrated using the most rigorous study design that the local clinical environment can support. Results of useful studies include both processes and outcomes of care, the latter including both objective and subjective measures. Comprehensive testing of EMR innovations requires a multispecialty team of investigators, adequate funding, and a commitment of both informaticists and clinicians. Demonstrating the beneficial effects of integrated EMR systems will facilitate their incorporation into everyday clinical care.

Controlled trial of direct physician order entry: effects on physicians' time utilization in ambulatory primary care internal medicine practices.

OBJECTIVE: Direct physician order entry (POE) offers many potential benefits, but evidence suggests that POE requires substantially more time than traditional paper-based ordering methods. The Medical Gopher is a well-accepted system for direct POE that has been in use for more than 15 years. The authors hypothesized that physicians using the Gopher would not spend any more time writing orders than physicians using paper-based methods. DESIGN: A randomized controlled trial of POE using the Medical Gopher system in 11 primary care internal medicine practices. MEASUREMENTS: The authors collected detailed time use data using time motion studies of the physicians and surveyed their opinions about the POE system. RESULTS: The authors found that physicians using the Gopher spent 2.2 min more per patient overall, but when duplicative and administrative tasks were taken into account, physicians were found to have spent only 0.43 min more per patient. With experience, the order entry time fell by 3.73 min per patient. The survey revealed that the physicians believed that the system improved their patient care and wanted the Gopher to continue to be available in their practices. CONCLUSIONS: Little extra time, if any, was required for physicians to use the POE system. With experience in its use, physicians may even save time while enjoying the many benefits of POE.

A randomized trial of "corollary orders" to prevent errors of omission.

OBJECTIVE: Errors of omission are a common cause of systems failures. Physicians often fail to order tests or treatments needed to monitor/ameliorate the effects of other tests or treatments. The authors hypothesized that automated, guideline-based reminders to physicians, provided as they wrote orders, could reduce these omissions. DESIGN: The study was performed on the inpatient general medicine ward of a public teaching hospital. Faculty and housestaff from the Indiana University School of Medicine, who used computer workstations to write orders, were randomized to intervention and control groups. As intervention physicians wrote orders for 1 of 87 selected tests or treatments, the computer suggested corollary orders needed to detect or ameliorate adverse reactions to the trigger orders. The physicians could accept or reject these suggestions. RESULTS: During the 6-month trial, reminders about corollary orders were presented to 48 intervention physicians and withheld from 41 control physicians. Intervention physicians ordered the suggested corollary orders in 46.3% of instances when they received a reminder, compared with 21.9% compliance by control physicians (p < 0.0001). Physicians discriminated in their acceptance of suggested orders, readily accepting some while rejecting others. There were one third fewer interventions initiated by pharmacists with physicians in the intervention than control groups. CONCLUSION: This study demonstrates that physician workstations, linked to a comprehensive electronic medical record, can be an efficient means for decreasing errors of omissions and improving adherence to practice guidelines.

Units of measure in clinical information systems.

The authors surveyed existing standard codes for units of measures, such as ISO 2955, ANSI X3.50, and Health Level 7's ISO+. Because these standards specify only the character representation of units, the authors developed a semantic model for units based on dimensional analysis. Through this model, conversion between units and calculations with dimensioned quantities become as simple as calculating with numbers. All atomic symbols for prefixes and units are defined in one small table. Huge permutated conversion tables are not required. This method is also simple enough to be widely implementable in today's information systems. To promote the application of the method the authors provide an open-source implementation of this method in JAVA. All existing code standards for units, however, are incomplete for practical use and require substantial changes to correct their many ambiguities. The authors therefore developed a code for units that is much more complete and free from ambiguities.

Computerizing guidelines to improve care and patient outcomes: the example of heart failure.

Increasing amounts of medical knowledge, clinical data, and patient expectations have created a fertile environment for developing and using clinical practice guidelines. Electronic medical records have provided an opportunity to invoke guidelines during the everyday practice of clinical medicine to improve health care quality and control costs. In this paper, efforts to incorporate complex guidelines [those for heart failure from the Agency for Health Care Policy and Research (AHCPR)] into a network of physicians' interactive microcomputer workstations are reported. The task proved difficult because the guidelines often lack explicit definitions (e.g., for symptom severity and adverse events) that are necessary to navigate the AHCPR algorithm. They also focus more on errors of omission (not doing the right thing) than on errors of commission (doing the wrong thing) and do not account for comorbid conditions, concurrent drug therapy, or the timing of most interventions and follow-up. As they stand, the heart failure guidelines give good general guidance to individual practitioners, but cannot be used to assess quality or care without extensive "translation" into the local environment. Specific recommendations are made so that future guidelines will prove useful to a wide range of prospective users.

Development of the Logical Observation Identifier Names and Codes (LOINC) vocabulary.

The LOINC (Logical Observation Identifier Names and Codes) vocabulary is a set of more than 10,000 names and codes developed for use as observation identifiers in standardized messages exchanged between clinical computer systems. The goal of the study was to create universal names and codes for clinical observations that could be used by all clinical information systems. The LOINC names are structured to facilitate rapid matching, either automated or manual, between local vocabularies and the universal LOINC codes. If LOINC codes are used in clinical messages, each system participating in data exchange needs to match its local vocabulary to the standard vocabulary only once. This will reduce both the time and cost of implementing standardized interfaces. The history of the development of the LOINC vocabulary and the methodology used in its creation are described.